US5704297A - Dry powder composition of hydroxyethyl starch suitable for reconstitution - Google Patents

Dry powder composition of hydroxyethyl starch suitable for reconstitution Download PDF

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Publication number
US5704297A
US5704297A US07/652,034 US65203491A US5704297A US 5704297 A US5704297 A US 5704297A US 65203491 A US65203491 A US 65203491A US 5704297 A US5704297 A US 5704297A
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Prior art keywords
hydroxyethyl starch
dry powder
molecular weight
powder composition
dextrose
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Expired - Fee Related
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US07/652,034
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Munir Alwan Hussain
Raghunath Srinivas
Lei-Shu Wu
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Bristol Myers Squibb Pharma Co
EIDP Inc
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DuPont Merck Pharmaceutical Co
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Priority to US07/652,034 priority Critical patent/US5704297A/en
Assigned to E. I. DU PONT DE NEMOURS AND COMPANY A CORP. OF DELAWARE reassignment E. I. DU PONT DE NEMOURS AND COMPANY A CORP. OF DELAWARE ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: HUSSAIN, MUNIR A., SRINIVAS, RAGHUNATH, WU, LEI-SHU
Priority to PCT/US1992/000571 priority patent/WO1992013915A1/en
Priority to AU12284/92A priority patent/AU1228492A/en
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Assigned to DUPONT PHARMACEUTICALS COMPANY reassignment DUPONT PHARMACEUTICALS COMPANY CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: DUPONT MERCK PHARMACEUTICAL COMPANY, THE
Assigned to BRISTOL-MYERS SQUIBB PHARMA COMPANY reassignment BRISTOL-MYERS SQUIBB PHARMA COMPANY CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: DUPONT PHARMACEUTICALS COMPANY
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0026—Blood substitute; Oxygen transporting formulations; Plasma extender
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/05—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media from solid polymers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L3/00—Compositions of starch, amylose or amylopectin or of their derivatives or degradation products
    • C08L3/04—Starch derivatives, e.g. crosslinked derivatives
    • C08L3/08—Ethers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2303/00—Characterised by the use of starch, amylose or amylopectin or of their derivatives or degradation products
    • C08J2303/04—Starch derivatives
    • C08J2303/08—Ethers

Definitions

  • HESPAN is a plasma volume expander, made as described in U.S. Pat. No. 3,523,938 and currently sold by E. I. du Pont de Nemours and Company, and which uses a fraction of hydroxyethyl starch known as hetastarch.
  • Hetastarch synthesized by the hydroxyethylation of polysaccharides, contains polymers of a wide range of sizes, 90% of which have a molecular weight of between about 10,000 and 1,000,000 and has a number average molecular weight of about 69,000.
  • Average molecular weight and molecular weight distribution are useful parameters in defining heterogeneous polymers such as hydroxyethyl starch. Polymer molecular weights are defined several different ways depending on the particular needs.
  • the number average molecular weight is the most useful term for the clinician concerned with oncotic pressures.
  • the oncotic pressure of hydroxyethyl starch is related to the number of macromolecules in solution and has been measured as 30 mm mercy. Oncotic pressures for various hydroxyethyl starches have been reported.
  • the number average molecular weight is defined as the number of molecules in the fraction having a specific molecular weight times the molecular weight divided by the number of molecules in the fraction. As mentioned before, hetastarch has been synthesized with a number average molecular weight of about 69,000.
  • the weight average molecular weight is useful to the chemist in defining the polymer resulting from a synthetic process. It is defined as the summation of the weights of individual fractions times the molecular weight of the species within the fractions divided by the sums of the weights of the individual fractions.
  • gel permeation chromatography has been used to determine molecular weight distribution and to estimate molecular weight.
  • the molecular weight ranges from 180 for one glucose unit to well over one million for the largest polymer molecule.
  • the distribution of molecules for hetastarch is such that at least 80% of the molecules have a molecular weight between ten thousand and two million.
  • the average molecular weight by gel permeation chromatography is approximately 450,000.
  • hydroxyethyl starch fractions with possibly varying characteristics are used for different purposes. As described, hetastarch is generally used for plasma volume expansion. Pentastarch, as described in U.S. Pat. No. 4,873,230, is used for leukophoresis. This fraction has a molecular weight of from about 150,000 to about 350,000, degree of substitution of from abut 0.4 to about 0.7, and is substantially free of ethylene glycol, ethylene chlorohydrin, sodium chloride and acetone.
  • An additional fraction as described in U.S. Pat. No. 4,798,824 issued Jan. 17, 1989, is intended for use in a perfusate for the preservation of organs or in a solution for the preservation of organs, as described in U.S. Pat. No. 4,879,283 issued Nov. 7, 1989.
  • This fraction has a molecular weight of from about 150,000 to about 350,000, a degree of substitution of from about 0.4 to about 0.7, being substantially free of ethylene glycol, ethylene chlorohydrin, sodium chloride and acetone, and being substantially free of hydroxyethyl starch having a molecular weight of less than about 50,000.
  • the present invention relates to a dry powder composition of hydroxyethyl starch suitable for reconstitution and comprising hydroxyethyl starch of a molecular weight of up to about 2,000,000, a degree of substitution of from about 0.4 to about 0.7, and containing less than about 0.5 parts by weight of ethylene glycol per 100 parts of the hydroxyethyl starch, the hydroxyethyl starch comprising from about 4% to about 40% by weight of the composition.
  • the composition includes at least one soluble component in addition to the hydroxyethyl starch.
  • the dry powder composition can be used for the preparation of formulations requiring hydroxyethyl starch and can be reconstituted just prior to use thereby reducing cost with regard to shipping and storage.
  • hydroxyethyl starch can be used for the dry powder composition, depending on the final solution desired and its purpose.
  • the solution rate of hydroxyethyl starch is slow. It has been found that mixing the hydroxyethyl starch with at least one soluble component, namely dextrose, lactose, mannitol or sodium chloride, enhances the dissolution rate so that the dry powder composition dissolves in about 6 minutes to about 8 minutes.
  • dextrose is preferred.
  • a dry powder composition would obviate the need for different size solutions, namely 125 ml, 500 ml, 1 liter, etc. which can be made as needed.
  • the dry powder composition would also be useful in disaster or crisis situations.
  • the dry powder composition can also be packaged by conventional powder fill equipment.
  • the reconstitution of the powder from the various preparations was conducted by placing 450 ml of water or saline solution into a 500 ml intravenous administration bottle containing pre-weighed powder which would make 10% pentastarch solution after reconstitution.
  • the bottles were shaken using a horizontal shaker with two inches shaking distance, at 168 shakes/minute.
  • the evaluation was rated on a scale of 1 to 6.
  • a geometric powder mixture of pentastarch and dextrose gave a promising result for improving the dissolution rate of the pentastarch. This is a simple and straight forward method and the powder mixture provides a faster reconstitution rate in the hospital as well as eases the in-house preparation of pentastarch solution.

Abstract

The present invention relates to a dry powder composition of hydroxyethyl starch suitable for reconstitution and comprising hydroxyethyl starch of a molecular weight of up to about 2,000,000, a degree of substitution of from about 0.4 to about 0.7, and containing less than about 0.5 parts by weight of ethylene glycol per 100 parts of the hydroxyethyl starch, the hydroxyethyl starch comprising from about 4% to about 40% by weight of the composition. The composition includes at least one soluble component in addition to the hydroxyethyl starch chosen from dextrose, lactose or mannitol.

Description

BACKGROUND OF THE INVENTION
Colloids are frequently used in the resuscitation of hypovolemic patients with shock. Potential benefits of maintaining or increasing plasma colloid osmotic pressure include the rapid restoration of the circulating plasma volume and the avoidance of excessive fluid accumulation, particularly in the lung U.S. Pat. No. 3,523,938 issued Aug. 11, 1970, for Starch Plasma Expanders and Process of Preparation describes the preparation and use of hydroxyethyl starch as a plasma volume expander. HESPAN is a plasma volume expander, made as described in U.S. Pat. No. 3,523,938 and currently sold by E. I. du Pont de Nemours and Company, and which uses a fraction of hydroxyethyl starch known as hetastarch. Hetastarch, synthesized by the hydroxyethylation of polysaccharides, contains polymers of a wide range of sizes, 90% of which have a molecular weight of between about 10,000 and 1,000,000 and has a number average molecular weight of about 69,000.
Average molecular weight and molecular weight distribution are useful parameters in defining heterogeneous polymers such as hydroxyethyl starch. Polymer molecular weights are defined several different ways depending on the particular needs.
The number average molecular weight is the most useful term for the clinician concerned with oncotic pressures. The oncotic pressure of hydroxyethyl starch is related to the number of macromolecules in solution and has been measured as 30 mm mercy. Oncotic pressures for various hydroxyethyl starches have been reported. The number average molecular weight is defined as the number of molecules in the fraction having a specific molecular weight times the molecular weight divided by the number of molecules in the fraction. As mentioned before, hetastarch has been synthesized with a number average molecular weight of about 69,000.
The weight average molecular weight is useful to the chemist in defining the polymer resulting from a synthetic process. It is defined as the summation of the weights of individual fractions times the molecular weight of the species within the fractions divided by the sums of the weights of the individual fractions.
Historically, gel permeation chromatography has been used to determine molecular weight distribution and to estimate molecular weight. The molecular weight ranges from 180 for one glucose unit to well over one million for the largest polymer molecule. The distribution of molecules for hetastarch is such that at least 80% of the molecules have a molecular weight between ten thousand and two million. For hetastarch the average molecular weight by gel permeation chromatography is approximately 450,000.
Various hydroxyethyl starch fractions with possibly varying characteristics are used for different purposes. As described, hetastarch is generally used for plasma volume expansion. Pentastarch, as described in U.S. Pat. No. 4,873,230, is used for leukophoresis. This fraction has a molecular weight of from about 150,000 to about 350,000, degree of substitution of from abut 0.4 to about 0.7, and is substantially free of ethylene glycol, ethylene chlorohydrin, sodium chloride and acetone.
An additional fraction, as described in U.S. Pat. No. 4,798,824 issued Jan. 17, 1989, is intended for use in a perfusate for the preservation of organs or in a solution for the preservation of organs, as described in U.S. Pat. No. 4,879,283 issued Nov. 7, 1989. This fraction has a molecular weight of from about 150,000 to about 350,000, a degree of substitution of from about 0.4 to about 0.7, being substantially free of ethylene glycol, ethylene chlorohydrin, sodium chloride and acetone, and being substantially free of hydroxyethyl starch having a molecular weight of less than about 50,000.
While specific fractions may be preferred for specific uses, use of the different fractions can be interchanged in some cases.
All of the current hydroxyethyl starch products are manufactured as solutions. A dry powder composition would be desirable as it would reduce costs with regard to shipping and storage as well as providing additional advantages.
SUMMARY OF THE INVENTION
The present invention relates to a dry powder composition of hydroxyethyl starch suitable for reconstitution and comprising hydroxyethyl starch of a molecular weight of up to about 2,000,000, a degree of substitution of from about 0.4 to about 0.7, and containing less than about 0.5 parts by weight of ethylene glycol per 100 parts of the hydroxyethyl starch, the hydroxyethyl starch comprising from about 4% to about 40% by weight of the composition. The composition includes at least one soluble component in addition to the hydroxyethyl starch.
The dry powder composition can be used for the preparation of formulations requiring hydroxyethyl starch and can be reconstituted just prior to use thereby reducing cost with regard to shipping and storage.
Specific fractions of hydroxyethyl starch can be used for the dry powder composition, depending on the final solution desired and its purpose.
DETAILED DESCRIPTION OF THE INVENTION
The solution rate of hydroxyethyl starch is slow. It has been found that mixing the hydroxyethyl starch with at least one soluble component, namely dextrose, lactose, mannitol or sodium chloride, enhances the dissolution rate so that the dry powder composition dissolves in about 6 minutes to about 8 minutes. The use of dextrose is preferred. By reconstituting the dry powder composition just prior to use, cost is reduced with regard to shipping and storage. Moreover, a dry powder composition would obviate the need for different size solutions, namely 125 ml, 500 ml, 1 liter, etc. which can be made as needed. The dry powder composition would also be useful in disaster or crisis situations. The dry powder composition can also be packaged by conventional powder fill equipment.
The feasibility of developing a dry powder formulation to improve the reconstitution rate of hydroxyethyl starch was investigated. Two approaches were studied.
(I) Mixing the hydroxyethyl starch with additives geometrically to separate the hydrxoyethyl starch particles and to enhance the wetting and dispersion during its reconstitution.
(II) Lyophilizing solutions of hydroxyethyl starch in the presence of additives (dextrose, sodium chloride, lactose or mannitol) to change the powder matrix properties and to enhance the reconstitution rate of pentastarch.
The reconstitution of the powder from the various preparations was conducted by placing 450 ml of water or saline solution into a 500 ml intravenous administration bottle containing pre-weighed powder which would make 10% pentastarch solution after reconstitution. The bottles were shaken using a horizontal shaker with two inches shaking distance, at 168 shakes/minute.
The evaluation was rated on a scale of 1 to 6.
1: All the powder dissolved in 6 minutes,
2: All the powder dissolved in 8 minutes,
3: All the powder dissolved in 10 minutes,
4: 5% remained undissolved at 6 minutes and all dissolved in 12 minutes,
5: 10% remained undissolved at 6 minutes and all dissolved in 14 minutes,
6: 25% remained undissolved at 6 minutes and 5% remained undissolved at 16 minutes.
The results are summarized as follows:
______________________________________                                    
                          Rating                                          
______________________________________                                    
Preparation A:                                                            
            Lyophilized powder from a                                     
                                4                                         
            solution of 10% pentastarch,                                  
            5% dextrose and 2% glycerol,                                  
            is a white, hard, and porous                                  
            cake.                                                         
Preparation B:                                                            
            Lyophilized powder from a                                     
                                6                                         
            solution of 10% pentastarch,                                  
            0.9% sodium chloride and 0.5%                                 
            glycerol, is a white, crispy,                                 
            and porous cake.                                              
Preparation C:                                                            
            Lyophilized powder from a                                     
                                3                                         
            solution of 10% pentastarch                                   
            and 0.5% glycerol, is a white,                                
            fluffy, porous cake.                                          
Preparation D:                                                            
            Lyophilized powder from a                                     
                                6                                         
            solution of 40% pentastarch                                   
            and 20% dextrose, is a clear,                                 
            glassy chip.                                                  
Preparation E:                                                            
            Lyophilized powder from a                                     
                                5                                         
            solution of 40% pentastarch                                   
            and 3.6% sodium chloride, is                                  
            a mixture of glassy and porous                                
            white cake.                                                   
Preparation F:                                                            
            Lyophilized powder from a                                     
                                5                                         
            solution of 40% pentastarch                                   
            and 2% glycerol, is a dense                                   
            white, and crispy cake                                        
            with no visible pore.                                         
Preparation H:                                                            
            A geometric mixture of penta-                                 
                                2                                         
            starch and dextrose.                                          
Preparation H':                                                           
            Same as preparation H; however,                               
                                2                                         
            spray dried pentastarch instead                               
            of drum dried being used.                                     
Preparation M:                                                            
            A powder mixture of pentastarch                               
                                1                                         
            and dextrose mixed using 1/2                                  
            quart V-blender, is a white free                              
            flowing powder.                                               
Preparation M':                                                           
            Same preparation as M; however,                               
                                2                                         
            spray dried pentastarch instead                               
            of drum dried being used.                                     
Preparation N:                                                            
            A powder mixture of pentastarch                               
                                5                                         
            and sodium chloride mixed using                               
            1/2 quart V-blender, is a white                               
            free flowing powder.                                          
Preparation N':                                                           
            Same preparation as N; however,                               
                                5                                         
            spray dried pentastarch instead                               
            of drum dried being used.                                     
Preparation O:                                                            
            A powder mixture of pentastarch,                              
                                2                                         
            dextrose, and sodium chloride                                 
            using 1/2 quarter V-blender, is a                             
            white free flowing powder.                                    
Preparation O':                                                           
            Same preparation as O; however,                               
                                3                                         
            spray dried pentastarch instead                               
            of drum dried being used.                                     
Control:    Reconstitution: 90% 5                                         
            Remained undissolved at 5 minutes.                            
______________________________________
A geometric powder mixture of pentastarch and dextrose gave a promising result for improving the dissolution rate of the pentastarch. This is a simple and straight forward method and the powder mixture provides a faster reconstitution rate in the hospital as well as eases the in-house preparation of pentastarch solution. The powder mixtures of pentastarch and dextrose, by using a small scale V-blender, showed a fast reconstitution rate also. This demonstrated that it is feasible to be scaled up and still keep the beneficial powder properties.
An example of a suitable formulation is as follows:
______________________________________                                    
Ingredient           Amount                                               
______________________________________                                    
Pentastarch          50     grams                                         
Mannitol             0-10   grams                                         
Sodium chloride      0-10   grams                                         
Dextrose             0-40   grams                                         
Water for injection  Q.5 to 500 ml                                        
______________________________________

Claims (6)

What is claimed is:
1. A dry powder composition comprising hydroxyethyl starch of a molecular weight of up to about 2,000,000 daltons, a degree of substitution of from about 0.4 to about 0.7 and containing less than about 0.5 parts by weight of ethylene glycol per 100 parts of the hydroxyethyl starch, and at least one water soluble component selected from dextrose, lactose, and mannitol, and characterized in that the powder dissolves within 8 minutes when 450 ml of water and sufficient powder to provide a 10% hydroxyethyl starch solution are placed in a 500 ml bottle and the bottle is shaken using a horizontal shaker with two inches shaking distance at 168 shakes per minute.
2. The dry powder composition of claim 1 wherein the water soluble component is dextrose.
3. The dry powder composition of claim 1 wherein the hydroxyethyl starch has a molecular weight of from about 150,000 daltons to about 350,000 daltons and is substantially free of ethylene glycol, ethylene chlorohydrin, sodium chloride and acetone.
4. The dry powder composition of claim 3 wherein the water soluble component is dextrose.
5. A dry powder composition comprising hydroxyethyl starch of a molecular weight of from about 150,000 to about 350,000, a degree of substitution of from about 0.4 to about 0.7, being substantially free of ethylene glycol, ethylene chlorohydrin, sodium chloride and acetone, and being substantially free of hydroxyethyl starch having a molecular weight less than 50,000, and at least one water soluble component selected from dextrose, lactose, and mannitol, and characterized in that the powder dissolves within 8 minutes when 450 ml of water and sufficient powder to provide a 10% hydroxyethyl starch solution are placed in a 500 ml bottle and the bottle is shaken using a horizontal shaker with two inches shaking distance at 168 shakes per minute.
6. The dry powder composition of claim 5 wherein the water soluble component is dextrose.
US07/652,034 1991-02-06 1991-02-06 Dry powder composition of hydroxyethyl starch suitable for reconstitution Expired - Fee Related US5704297A (en)

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US07/652,034 US5704297A (en) 1991-02-06 1991-02-06 Dry powder composition of hydroxyethyl starch suitable for reconstitution
PCT/US1992/000571 WO1992013915A1 (en) 1991-02-06 1992-02-04 Dry powder composition of hydroxyethyl starch suitable for reconstitution
AU12284/92A AU1228492A (en) 1991-02-06 1992-02-04 Dry powder composition of hydroxyethyl starch suitable for reconstitution

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EP1190719A1 (en) * 2000-08-17 2002-03-27 B. Braun Melsungen Ag Colloidal pharmacomodulation of injected pharmaceutical compositions
EP1230935A2 (en) * 2001-02-09 2002-08-14 B. Braun Melsungen Ag Modified colloids and their use
US20030138437A1 (en) * 2000-02-08 2003-07-24 Allergan, Inc. Reduced toxicity clostridial toxin pharmaceutical compositions
US20060104994A1 (en) * 2000-02-08 2006-05-18 Hunt Terrence J Clostridial toxin pharmaceutical composition containing a gelatin fragment
US20060269575A1 (en) * 2000-02-08 2006-11-30 Allergan, Inc. Botulinum toxin pharmaceutical compositions formulated with recombinant albumin
US20080213315A1 (en) * 2000-02-08 2008-09-04 Allergan, Inc. Clostridial toxin pharmaceutical compositions
US7579010B2 (en) 2000-02-08 2009-08-25 Allergan, Inc. Botulinum toxin pharmaceutical compositions with a recombinant human serum albumin
US20110237542A1 (en) * 2008-12-01 2011-09-29 Shin Poong Pharmaceutical Co., Ltd. Composition for preventing adhesion

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DE2700011A1 (en) * 1977-01-03 1978-07-06 Hideo Omoto Prodn. of hydroxyethyl starch for use as plasma substitute - from waxy starch by reaction with ethylene oxide then controlled acid hydrolysis
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US3523938A (en) * 1967-12-13 1970-08-11 American Hospital Supply Corp Starch plasma expanders and process of preparation
US3960584A (en) * 1973-02-02 1976-06-01 The Dow Chemical Company Water-dispersible, high molecular weight polymer compositions
US3951949A (en) * 1973-07-12 1976-04-20 Ajinomoto Co., Inc. Sulfates of hydroxyethyl starch
US4076547A (en) * 1976-06-10 1978-02-28 Polymerics, Inc. Polymeric molding composition
US4306059A (en) * 1977-09-30 1981-12-15 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo Shaped products of alpha-glucan
US4435217A (en) * 1982-04-22 1984-03-06 Venture Innovations, Inc. Concentrated hydrophilic polymer suspensions
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080213315A1 (en) * 2000-02-08 2008-09-04 Allergan, Inc. Clostridial toxin pharmaceutical compositions
US9302008B2 (en) 2000-02-08 2016-04-05 Allergan, Inc. Pharmaceutical compositions containing botulinum toxin
US7579010B2 (en) 2000-02-08 2009-08-25 Allergan, Inc. Botulinum toxin pharmaceutical compositions with a recombinant human serum albumin
US20030138437A1 (en) * 2000-02-08 2003-07-24 Allergan, Inc. Reduced toxicity clostridial toxin pharmaceutical compositions
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